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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
Simone de Jong, Mateus Jose Abdalla Diniz, Andiara Saloma, Ary Gadelha, Marcos Santoro, Vanessa Ota, Cristiano Noto, Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J. Adams, Esben Agerbo, Tracy Air, Till F. M. Andlauer, Silviu‐Alin Bacanu, Marie Bækvad‐Hansen, Aartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Douglas Blackwood, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg‐Grauholm, Na Cai, Enrique Castelao, Jane Christensen, Toni‐Kim Clarke, Jonathan R. I. Coleman, Lucía Colodro‐Conde, Baptiste Couvy‐Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Ian J. Deary, Franziska Degenhardt, Eske M. Derks, Neşe Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott‐Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Andreas J. Forstner, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Christine Søholm Hansen, Thomas Folkmann Hansen, Stefan Herms, Ian B. Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke‐Jan Hottenga, David M. Hougaard, Marcus Ising, Ian Jones, Lisa Jones, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick J. McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Högni Óskarsson, Michael J. Owen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Giorgio Pistis, Daniëlle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Margarita Rivera, Saira Saeed Mirza, Robert A. Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Engilbert Sigurðsson, Grant Sinnamon, Johannes H. Smit, Daniel J. Smıth, Hreinn Stefánsson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley K. Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Shantel Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin Simon Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T. Baune, Dorret I. Boomsma, Sven Cichon, Udo Dannlowski, Eco J. C. de Geus, J. Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Kenneth S. Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S. Li, Susanne Lucae, Pamela A. F. Madden, Patrik K. E. Magnusson, Nicholas G. Martin, Andrew M. McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller‐Myhsok, Merete Nordentoft, Markus M. Nöthen, Michael O‘Donovan, Sara A. Paciga, Nancy L. Pedersen, Brenda W.J.H. Penninx, Roy H. Perlis, David J. Porteous, James B. Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas G. Schulze, Jordan W. Smoller, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M. Weissman, Thomas Werge, Cathryn M. Lewis, Douglas F. Levinson, Anders D. Børglum, Patrick F. Sullivan, Sandra Meier, John S. Strauss, Wei Xu, John B. Vincent, K. Matthews, Manuel A. R. Ferreira, Colm O’Dushlaine, Shaun Purcell, Soumya Raychaudhuri, Douglas M. Ruderfer, Pamela Sklar, Laura J. Scott, Matthew Flickinger, Margit Burmeister, Jun Z. Li, Weihua Guan, Devin Absher, Robert C. Thompson, Fan Guo Meng, Alan F. Schatzberg, William E. Bunney, Jack D. Barchas, Stanley J. Watson, R Myers, Huda Akil, Michael Boehnke, Kimberly Chambert, Jennifer L. Moran, Edward M. Scolnick, Srdjan Djurovic, Ingrid Melle, Gunnar Morken, Aiden Corvin, Adebayo Anjorin, Radhika Kandaswamy, Jacob Lawrence, Alan McLean, Ben Pickard, Sarah E. Bergen, Vishwajit L. Nimgaonkar, Mikael Landén, Martin Schalling, Urban Ösby, Lena Backlund, Louise Frisén, Niklas Långström, Eli Stahl, Amanda Dobbyn, Stéphane Jamain, Bruno Étain, Frank Bellivier, Markus Leber, Anna Maaser, Sascha B. Fischer, Céline S. Reinbold, Sarah Kittel‐Schneider, Janice M. Fullerton, Lilijana Oruč, Fermín Mayoral, Fabio Rivas, Piotr M. Czerski, Jutta Kammerer-Ciernioch, Helmut Vedder, Margitta Borrmann-Hassenbach, Andrea Pfennig, Paul Brennan, James McKay, Manolis Kogevinas, Markus Schwarz, Peter R. Schofield, Thomas W. Mühleisen, Johannes Schumacher, Michael Bauer, A. Jordan Wright, Philip B. Mitchell, Martin Hautzinger, John R. Kelsoe, Tiffany A. Greenwood, Caroline M. Nievergelt, Paul D. Shilling, Erin N. Smith, Cinnamon S. Bloss, Howard J. Edenberg, Daniel L. Koller, Elliot S. Gershon, Chunyu Liu, Judith A. Badner, William A. Scheftner, William Lawson, Evaristus Nwulia, Maria Hipolito, William Coryell, William Byerley, Francis J. McMahon, Falk W. Lohoff, Peter P. Zandi, Pamela B. Mahon, Melvin G. McInnis, Sebastian Zöllner, Peng Zhang, Szabolcs Szelinger, David St Clair, Sian Caesar, Katherine Gordon‐Smith, Christine Fraser, Elaine Green, Detelina Grozeva, Marian L. Hamshere, George Kirov, Ivan Nikolov, David Collier, Amanda Elkin, Richard Williamson, Allan H. Young, I. Nicol Ferrier, Vihra Milanova, Martin Alda, Pablo Cervantes, Cristiana Cruceanu, Guy A. Rouleau, Gustavo Turecki, Ashley R. Winslow, Maria Grigoroiu‐Serbânescu, Roel A. Ophoff, Rolf Adolfsson, Annelie Nordin Adolfsson, Jurgen Del‐Favero, Carlos N. Pato, Joanna M. Biernacka, Mark A. Frye, Derek W. Morris, Nicholas J. Schork, Andreas Reif, Jolanta Lissowska, Joanna Hauser, Neonila Szeszenia‐Dąbrowska, Kevin A. McGhee, Emma M. Quinn, Valentina Moskvina, Peter Holmans, Anne Farmer, James L. Kennedy, Ole A. Andreassen, Morten Mattingsdal, Nicholas Bass, Hugh Gurling, Andrew McQuillin, René Breuer, Christina M. Hultman, Paul Lichtenstein, Laura M. Huckins, Marion Leboyer, Mark Lathrop, John I. Nürnberger, Michael Steffens, Tatiana Foroud, Wade H. Berrettini, David W. Craig, Jianxin Shi, Charles Curtis, Stephen Newhouse, Hamel Patel, Lynsey S. Hall, Paul F. O’Reilly, Síntia Belangero, Rodrigo A. Bressan, Gerome Breen
Bibliographic record
VenueCommunications Biology · 2018
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsMcGill UniversityMcGill University Health CentrePrincess Margaret Cancer CentreMontreal Neurological Institute and HospitalDalhousie UniversityUniversity of TorontoCentre for Addiction and Mental HealthMcGill University and Génome Québec Innovation CentrePublic Health OntarioUniversity of British Columbia
FundersCilagFP7 People: Marie-Curie ActionsEconomic and Social Research CouncilNational Institute for Health and Care ResearchDaiichi-SankyoFundação de Amparo à Pesquisa do Estado de São PauloBritish Heart FoundationUniversity College LondonLundbeckfondenCancer Research UKWellcome TrustMedical Research CouncilNational Institute of Mental HealthNational Institute for Social Care and Health ResearchEngineering and Physical Sciences Research CouncilEli Lilly and Company
KeywordsBipolar disorderAnticipation (artificial intelligence)Assortative matingPedigree chartPolygenic risk scoreMajor depressive disorderPsychiatryMood disordersPsychologyMoodClinical psychologyMedicineGeneticsBiologyMatingGenotypeSingle-nucleotide polymorphism
Abstract
Abstract Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.630
Threshold uncertainty score0.698
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.012
GPT teacher head0.293
Teacher spread0.281 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations25
Published2018
Admission routes1
Has abstractyes